Endocrine Abstracts

In late pregnancy the mother must mobilise considerable energy stores to support fetal growth. Failure to appropriately nourish the fetus has significant obstetric consequences – gestational diabetes and fetal growth restriction (FGR). Despite this, relatively little is known about how metabolic responses are stimulated in the mother, and how they may go wrong. We previously found that high levels of the product of an imprinted gene, Delta-like homologue-1 (Dlk1), circulate in maternal blood in late gestation, and that the fetus is the source of this protein. By manipulating maternal DLK1 levels in mice we demonstrated that DLK1 is a fetal signal that mediates the maternal response to starvation by activation of the ketogenic pathway. We hypothesised that low DLK1 might be a clinically relevant marker to predict restricted growth in human pregnancy, and indeed found that low DLK1 is associated with FGR. Our first case-control study finding has since been replicated by others, and in our larger population-based study. We are currently exploring how the cis-regulatory landscape influences Dlk1 expression in both normal development and disease, and investigating the molecular physiology of DLK1 signalling. We will present data that indicates that DLK1 has a direct impact on placental hormone production and that as a consequence, alteration of Dlk1 gene dosage impacts maternal adipose storage and mobilisation - key processes that ensure adequate nutrient provision to the growing fetus.